Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular patterns

Abstract

Recent research has led to contradictory notions regarding the conventional theory that apoptotic cell death can evoke inflammatory or immunogenic responses orchestrated by released damage-associated patterns (DAMPs). By inducing IL-1β from bone marrow-derived macrophages in an effort to determine the inflammatory mediators released from apoptotic cells, we found that exosomal fractions called “apoptotic exosome-like vesicles” (AEVs) prepared from apoptotic-conditioned medium were the main inflammatory factors. These AEVs showed characteristics of exosomes in their size, density, morphology, and protein expression but had unique marker proteins, sphingosine-1-phosphate receptors 1 and 3 (S1PR1 and 3). Their biogenesis was completely dependent on cellular sphingosine-1-phosphate (S1P)/S1PRs signaling from multiple fine spindles of plasma membrane accompanied by F-actin, S1PR1, S1PR3, and CD63 at the early apoptotic phase and progressing to the maturation of F-actin–guided multivesicular endosomes mediated by Gβγ subunits of S1PRs downstream. S1P-loaded S1PRs on AEVs were critical factors for inducing IL-1β via NF-κB transcriptional factor and p38 MAPK, possibly through the RHOA/NOD2 axis, in differentiating macrophages. The AEVs induced genes of proinflammatory cytokines, chemokines, and mediators in both in vitro and in vivo models. In conclusion, AEVs could be key inflammatory mediators, acting as DAMPs that could explain the pathogeneses of various chronic inflammations, autoimmune diseases, or cancers in the future.

The Role of Lipopolysaccharide-Induced Extracellular Vesicles in Cardiac Cell Death

“…Caspases are a family of proteases that play a role in programmed cell death and inflammation. A study conducted by Park et al concluded that the release of exosomes is dependent upon caspases, particularly caspase 3 and caspase 9 [33]. In our study, we showed that both cleaved caspase 3 and cleaved caspase 9 expression were not altered after LPS treatment.…”

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…However, Hagen et al (2009) have demonstrated that only SphK2-mediated production of S1P can lead to apoptosis, indicating the role of subcellular localization of S1P in determining its biological function. Moreover, the key molecules in S1P-related signalings, such as the AP-1, ERK, or NF-κB, also play an ambiguous role in regulating cell apoptosis, thus exerting a dual effect on cell fate (Oh et al, 2017;Park et al, FIGURE 1 | Lysophosphatidic acid (LPA) as a promoter in Alzheimer's disease (AD) related neurodegeneration. LPA can elevate the binding activity of cAMP response element-binding protein (CREB) with β-site of amyloid precursor protein (APP)-cleaving enzyme (β-secretase, BACE 1) promoter at the CRE site through the G α/i -PKCδ-MEK-MAPK-p90RSK-CREB signaling pathway.…”

Circulating Small Noncoding RNAs Have Specific Expression Patterns in Plasma and Extracellular Vesicles in Myelodysplastic Syndromes and Are Predictive of Patient Outcome

“…These AEVs appear to be more than just debris and should be considered a key mechanism for apoptotic cells to communicate with surrounding cells. Moreover, they have important immune regulatory roles that differ from the functions of classical EVs [69,70] and might be relevant for the pathogenesis of various inflammatory diseases, including autoimmune diseases, cancers, and even MDS.…”